D2 dopamine receptor subtype-mediated hyperactivity and amphetamine responses in a model of ADHD

• Type of Material: Article
• Authors: Xueliang Fan, Emory University; Ming Xu, University of Chicago; Ellen Hess, Emory University
• Language: English
• Date: 2010-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.nbd.2009.10.009
• Title of Journal or Parent Work: Neurobiology of Disease
• ISSN: 0969-9961
• Volume: 37
• Issue: 1
• Start Page: 228
• End Page: 236
• Grant/Funding Information: Supported by U.S. Public Health Service Grant R01 NS34845.
• Keywords: coloboma; L-741; amphetamine; microdialysis; D4 dopamine receptor; 626; D2 dopamine receptor; ADHD; S33084; L-745; SNAP-25; 870; hyperactivity; D3 dopamine receptor; knockout
• Research Categories: Biology, Neuroscience

Abstract

Low doses of psychostimulants produce beneficial behavioral effects in ADHD patients but the mechanisms underlying the response are not understood. Here we use the hyperactive mouse mutant coloboma to identify D2-like dopamine receptor subtypes that mediate the hyperactivity and response to amphetamine; we have previously demonstrated that D1-like dopamine receptors are not involved. Targeted deletion of the D2, but not the D3 or the D4, dopamine receptor in coloboma mice eliminated the hyperactivity; depleting D2 dopamine receptors also restored the excess dopamine overflow that may drive the hyperactivity to normal concentrations. Similar to its effects on ADHD patients, amphetamine reduced the hyperactivity of coloboma mice. The D2 dopamine receptor-selective antagonist L-741,626, but not D3 or D4 dopamine receptor-selective antagonists, blocked the amphetamine-induced reduction in locomotor activity. Thus, the D2 dopamine receptor subtype mediates the both the hyperactivity and response to amphetamine, suggesting a specific target for novel therapeutics in ADHD.